Project Abstract Acute kidney injury (AKI) is one of the most common types of organ dysfunction among persons in the intensive care unit (ICU). Most causes of AKI involve injury to the proximal tubules of the kidneys. However, clinical evaluation of AKI relies on measurements of serum creatinine as a marker of glomerular filtration. Consequently, the severity and clinical implications of AKI may be misaligned with the biology of the disease. Proximal tubular secretory clearance is rarely measured due to a lack of reliable methods and uncertainty regarding clinical interpretation. We developed a novel targeted mass spectrometric assay to estimate tubular secretory clearance based on quantification of endogenous secretory solutes in plasma and urine, and we demonstrated that tubular secretory clearance is associated with the progression of chronic kidney disease and mortality independent of the estimated glomerular filtration rate. The general goal of this application is to advance clinical assessment of AKI by adding functional measurements that align with the underlying mechanisms of disease. We propose to measure tubular secretory clearances in a prospective cohort of critically ill adults who are at high risk for developing AKI. We will assess potential shared and unique risk factors for decline in tubular secretion and glomerular filtration, determine whether tubular secretory clearance adds to the prediction of measured drug levels, and test whether lower secretory clearance is associated with ICU delirium, coma and the severity and prognosis of AKI. 1